Reticuloendothelial iron overload is associated with secondary hemochromatosis including repeated transfusions and iron over-supplementation. Ferroportin disease B is a severe subtype of hereditary iron overload syndrome with an activated reticuloendothelial system. The iron exporter ferroportin may be insensitive to hepcidin 25 in this subtype. However, the interactions between the hepcidin-ferroportin system and modifiers of reticuloendothelial iron overload have not yet been elucidated. We describe two patients with iron overload conditions that were compatible with ferroportin disease B, but their genetic backgrounds and habitual states differed. Both patients had diabetes, periportal fibrosis with severe iron deposits in their hepatocytes and Kupffer cells, and adequate levels of circulating hepcidin 25. However, the first patient was heterozygous for a mutation in the FP gene and free from the acquired factors of iron overload, while the second patient was a heavy drinker with a heterozygous mutation in the TFR2 gene and no mutations in the FP gene. The first patient was the second reported case of ferroportin disease B in Japan. Our study on these 2 patients suggests that liver fibrosis associated with compound iron overload of reticuloendothelial cells and hepatocytes may occur via multi-etiological backgrounds.